CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL ... OffLab… · IVIG = Intravenous immunoglobulin; SCIG = Subcutaneous immunoglobulin. Exclusion Criteria Articles were excluded

Service Line: Rapid Response Service

Version: 1.0

Publication Date: April 30, 2018

Report Length: 19 Pages

CADTH RAPID RESPONSE REPORT:

SUMMARY WITH CRITICAL APPRAISAL

Off-Label Use of Intravenous

Immunoglobulin for Solid

Organ Transplant Rejection:

A Review of Clinical

Effectiveness

SUMMARY WITH CRITICAL APPRAISAL Of f -Label Use of IVIG f or Solid Organ Transplant Rejection 2

Authors: Sara D. Khangura, Sarah Visintini

Cite As: Off-label use of intravenous immunoglobulin for solid organ transplant rejection: a review of clinical effectiveness. Ottawa: CADTH; 2018 Apr. (CADTH

rapid response report: summary with critical appraisal).

ISSN: 1922-8147 (online)

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Abbreviations

AMR Antibody-mediated rejection

CADTH Canadian Agency for Drugs and Technologies in Health

DSA Donor-specific antibodies

eGFR Estimated glomerular filtration rate

GFR Glomerular filtration rate

IgG Immunoglobulin G

IV Intravenous

IVIG Intravenous immunoglobulin

MDRD Modified Diet in Renal Disease

MFI Mean fluorescence intensity

MP Methylprednisolone

RCT Randomized controlled trial

RTX Rituximab

SCID Subcutaneous immunoglobulin


Context and Policy Issues

The transplantation of solid organs — including heart, kidney, liver, lungs , and pancreas1

— has advanced significantly since the m iddle of the 20th century, with important and often

life-saving benefits to patients with a variety of conditions.2 In 2016, the Canadian Institute

for Health Information estimates that 2,906 solid organ transplants occurred in Canada.3

Despite important advances in the success of solid organ transplantation, rejection of

transplanted organs remains an important barrier. Organ transplant rejection occurs when

a patient’s immune system recognizes and attacks cells and tissues from the donor organ.4

Risk factors for organ transplant rejection include prior pregnancy, blood transfusion, and

past transplants.5 Organ transplant rejection can be experienced by the patient as a feeling

ill (e.g., malaise, nausea, fever) and can result in loss of the transplanted organ.4 Rejection

can occur at various points in time, manifesting as either acute (i.e., from during the

procedure, up to three months afterward) or chronic (i.e., more than three months following

the procedure) conditions.6

Treatment for acute transplant rejection has focused on the use of immunosuppressant

therapy to reduce the immune system’s rejection response to the donor tissue and avoid

loss of the transplanted organ — though, this approach is less effective in cases of chronic

organ transplant rejection.7 In cases of antibody-mediated rejection, current treatments

include plasmapheresis, proteasome inhibitors, complement inhibition, rituximab, and

intravenous immunoglobulin (IVIG), though research evaluating these treatments to-date

remains scarce and consists mostly of case reports and small case series of retrospective

cohort studies.5 While significant advances have been realized, particularly over the past

30 years,2 long-term benefits of existing treatments have not been consistently

demonstrated.8

Immunoglobulin (also referred to as immune globulin or gamma globulin) is a purified blood

product pooled from the plasma of healthy blood donors.9 Immunoglobulin may be

administered as IVIG or as subcutaneous immunoglobulin (SCIG). In Canada, various

preparations of immunoglobulin are approved specifically for use in patients with one or

more of the following six conditions: primary immune deficiency, immune thrombocytopenic

purpura, secondary immune deficiency states, chronic inflammatory demyelinating

polyneuropathy, Guillain-Barré Syndrome, and multifocal motor neuropathy.10 The products

approved for use are ANTHRASIL, Flebogamma, Octagam, Cutaquig (subcutaneous), and

WinRho SDF.10,11 Others approved for marketing are Atgam, Cytogam, Gammagard,

Gamunex, Hepagam B, Igivnex, Panzyga, Privigen, and Varizig. 10,11

Between 1998 and 2006, Canada’s per capita use of IVIG grew 115%, which makes

Canada one of the highest consumers of IVIG per capita worldwide.12-14 The belief is that

much of this growth is attributable to an increase in off-label use of IVIG.12,13,15 A three

month audit in 2007 conducted by the Ontario Regional Blood Coordinating Network found

that: 50% of IVIG use was on-label; 40% was off-label, but potentially clinically effective,

and; 10% was off-label and possibly not clinically effective.16 In Canada (except Quebec),

Canadian Blood Services supplies IVIG to hospitals at no charge; however, there is no

formal mechanism for oversight regarding IVIG use.13,15,16 Each dose of IVIG can cost

between $550 and $2,200 CAD per child and between $2,000 and $8,000 CAD per adult;

this does not include other associated costs of treatment.12 From April 2005 to March 2006,

this IVIG use cost Canadian Blood Services $196.1 million CAD.13


IVIG has been identified as a potentially beneficial therapy for patients experiencing solid

organ transplant rejection.17 The purpose of this report is to provide a synthesis of the

available evidence on the clinical effectiveness of off-label use of IVIG for solid organ

transplant rejection. This report is complementary to a 2017 CADTH Rapid Response,

Summary of Abstracts report: “Off-Label Use of Intravenous Immunoglobulin for Solid

Organ Transplant Rejection, Paraneoplastic Disorders, or Recurrent Miscarriage: Clinical

Effectiveness”.18

Research Questions

What is the clinical effectiveness of off-label use of intravenous or subcutaneous immunoglobulin for the treatment of solid organ transplant rejection?

Key Findings

One randomized controlled trial and one non-randomized, retrospective, observational

study were identified describing the clinical effectiveness of off-label use of intravenous

immunoglobulin for the treatment of solid organ transplant rejection. Evidence of moderate

quality from one randomized controlled trial investigating intravenous immunoglobulin

combined with rituximab versus placebo in 25 renal transplant patients with chronic

antibody mediated rejection indicated that there was no important effect on renal function.

Evidence of limited quality from one non-randomized, retrospective observational study

investigating intravenous immunoglobulin versus methylprednisolone in 39 renal transplant

patients with antibody mediated rejection indicated that there was a significant improvement

in renal function. Further evidence from larger, long-term studies, including investigating

other types of organ transplants, is necessary to reduce uncertainty.

Methods

Literature Search Methods

A limited literature search was conducted on key resources including PubMed, The

Cochrane Library, University of York Centre for Reviews and Dissemination (CRD)

databases, Canadian and major international health technology agencies, as well as a

focused Internet search. Methodological filters were applied to limit retrieval to health

technology assessments, systematic reviews, meta-analyses, randomized controlled trials,

and non-randomized studies. Where possible, retrieval was limited to the human

population. The search was also limited to English language documents published between

January 1, 2012 and October 26, 2017.

Selection Criteria and Methods

One reviewer screened all citations returned from the literature searches. In the first phase

of screening, titles and abstracts were reviewed for relevance and those deemed to be

potentially relevant were then retrieved18 and later assessed for eligibility by another

reviewer using full-text.

The inclusion of sources at the full-text level of screening was based on the eligibility criteria

outlined in Table 1.


Table 1: Selection Criteria

Population Patients any age with acute rejection and antibody-mediated rejection after solid organ transplantation

Intervention Human IVIG or SCIG products, including but not limited to those available in Canada, alone or in combination with corticosteroids or other immunomodulation therapy.

Comparator Treatment as usual, placebo, or no treatment

Outcomes Clinical benefits and harms

Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, non-randomized studies

IVIG = Intrav enous immunoglobulin; SCIG = Subcutaneous immunoglobulin.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, did not

use a comparative design, were duplicate publications, or were published prior to 2012.

Critical Appraisal of Individual Studies

The included studies were critically appraised by one reviewer using the Downs and Black

checklist, which is applied using 26 items across five sub-scales to assess reporting,

external validity, bias, confounding, and power.19 Summary scores were not calculated for

the included studies; rather, a review of the strengths and limitations of each included study

were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 456 citations were identified in the literature search. Following screening of titles

and abstracts, 432 citations were excluded and 24 potentially relevant reports from the

electronic search were retrieved for full-text review. No potentially relevant publications

were retrieved from the grey literature search. Of these potentially relevant articles, 22

publications were excluded for various reasons, and two publications met the inclusion

criteria and were included in this report. These comprised one RCT and one non-

randomized clinical trial. Appendix 1 presents the PRISMA flowchart of the study selection.

Additional references of potential interest are provided in Appendix 5.

Summary of Study Characteristics

Study Design

One multi-centre, double-blind randomized controlled trial (RCT)20 and one single-centre,

non-randomized, retrospective, comparative observational study21 were identified.

Country of Origin

The RCT was conducted in Spain20 and the non-randomized study was conducted in

Poland.21


Patient Population

Patients participating in the RCT20 were 25 kidney transplant recipients with chronic,

antibody-mediated rejection (AMR). The mean age in the intervention arm was 47 (± 13)

years and in the comparison arm was 49 (± 15) years. Ten of the 25 patients (40%)

participating in the RCT were female.

Patients evaluated in the non-randomized study21 were 39 kidney transplant recipients with

AMR. The mean age in the intervention arm was 40.64 (± 11.23) years and in the

comparison arm was 37.45 (± 11.61) years. Eighteen of the 39 patients (46%) participating

in the non-randomized study were female.

Interventions and Comparators

The RCT compared IVIG plus rituximab (RTX) versus placebo. Patients randomized to

receive IVIG plus RTX were administered IVIG at a dose of 0.5 grams (g)/ kilogram (kg)

once every three weeks for a total of four doses, as well as a single dose of RTX at a dose

of 375 milligrams (mg)/ metre2 (m) one week following the last dose of IVIG. Patients

randomized to placebo received an isovolumetric saline solution using the same schedule

as patients randomized to IVIG plus RTX.20

The non-randomized study compared IVIG versus methylprednisolone (MP). Patients

receiving IVIG were administered between one and three g/kg for two consecutive days, as

well as intravenous (IV) MP, antihistamine, and basic immunosuppression. Patients

receiving MP were administered IV MP at a dose of 500 mg for three consecutive days, as

well as prednisone and basic immunosuppression.21

Outcomes

Renal function was the primary outcome of interest in both the RCT20 and the non-

randomized study.21 In the RCT, renal function was measured primarily by the estimated

glomerular filtration rate (GFR) which was calculated using the Modified Diet in Renal

Disease (MDRD) equation in mL/min per 1.73 m2. Serum creatinine was also measured

using mg/decilitre (dL). Secondary measures of renal function included proteinuria (g/day),

renal lesions characterized (using Banff criteria), donor-specific antibodies (DSA) reported

as mean fluorescence intensity (MFI) and adverse events, including graft loss and/or death.

The duration of follow-up was one year.

Measures of renal function reported in the non-randomized study21 included the change in

estimated glomerular filtration rate (GFR) across time using the MDRD formula and

modeled using a mixed, generalized linear method. Serum creatinine was also reported as

a measure of interest using mg/dL. Adverse events were neither pre-specified as an

outcome of interest nor reported in the results, however, mention was made of side effects

in the discussion section of the paper. Duration of follow-up varied across patients — from

1.88 to 34.11 months in the IVIG group and 4.7 to 75.76 months in the control group — due

to the retrospective design of the study.

The beneficial direction of effect for the primary outcome was implied in both papers as

being a reduction in GFR.20,21 While a minimally important clinical difference was not

explicitly reported a priori, authors of the RCT20 described in the paper’s discussion that the

planned sample size was based, in part, on identifying a 10 ±10 millilitre (mL)/ minute (min)

per 1.73 m2 difference between groups (which implicates a minimally important clinical

difference). Minimally important clinical difference was not addressed in the non-


randomized study; though the authors did make it clear that a reduction in the linear slope

of GFR across time was evidence of a benefit to patients .21

Additional details regarding the characteristics of included publications are provided in

Appendix 2.

Summary of Critical Appraisal

Both studies in this review clearly reported their objectives, patient characteristics,

interventions and outcomes of interest.20,21 However, while the RCT20 clearly reported the

main findings, random variability in the data, losses to follow-up, and actual probability

values, the non-randomized study21 did not clearly report on these items. For both studies

in this review, neither a list of confounders nor a list of adverse events was reported. Clarity

of reporting is critical to a transparent assessment of the strengths and limitations of

studies. Because some information was lacking from the reports of the studies included in

this review, they could not be assessed in their entirety.

It was not possible to assess any of the items addressing external validity for the included

RCT20 as details about the representativeness of subjects asked to participate, patients

who consented to participate and the interventions administered were not reported.

Similarly, the non-randomized study did not report information on the representativeness of

the subjects included in the study, nor the interventions administered, but whereas the RCT

reported a patient flow diagram (but failed to validate representativeness), the non-

randomized study did not describe any relevant details concerning the selection of patients .

In order to understand whether and how the findings of a study may apply to other, similar

patients, an assessment of external validity is essential. Because external validity could not

be ascertained for either study, it remains unclear whether their findings can appropriately

be applied to other, similar patients.

The risk of bias was assessed as low in the RCT,20 with subjects and outcome assessors

blinded to the intervention received, no apparent unplanned analyses reported, consistent

follow-up duration across patients, ostensibly appropriate statistical analyses, reasonable

compliance and transparent reporting of losses to follow-up (as well as the use of intention-

to-treat analyses) and the use of apparently appropriate outcome measures. While the non-

randomized study likewise reported no apparently unplanned analyses, statistical

adjustment for inconsistent follow-up duration across patients, and otherwise apparently

appropriate statistical analyses, it is unlikely that patients and outcome assessors were

blinded to the interventions due to the investigators’ use of a retrospective method. Further,

there was nothing reported concerning compliance with the intervention and the outcome

measures were not clearly described. In this review, the retrospective design used in the

non-randomized study is an important consideration when weighing the internal validity of

its reported findings; thus, it should be interpreted with caution as bias may have had an

impact on the effects reported.

The RCT addressed confounding by recruiting patients within the same timeframe,

employing a randomized design that was concealed from patients and care providers, and

accounting for loss to follow-up.20 However, it was unclear whether the RCT recruited

patients for the intervention and comparison groups from the same or different centres, and

there was no explicit description of confounding variables. In the non-randomized study,21 it

was clear that patients in both groups were selected from a single centre; however, there

was no clear description of confounding variables or loss to follow-up. Further, it was clear

that patients were treated at variable points across time and that there was no


randomization undertaken due to the investigators’ use of a retrospective method. The

potential for confounding is an important threat to internal validity as well, and is essential

for study investigators to consider — particularly when using a non-randomized approach.

While the RCT in this review did not explicitly report potential confounders, its use of a

randomized design is an important strength that stands in contrast to the method employed

in the non-randomized study. The non-randomized study’s failure to explicitly discuss

potential confounding variables is another important limitation.

Finally, sample sizes in both studies were small and study power was acknowledged as a

limitation by the authors of both studies.20,21 Power calculations are critical as part of

considering an adequate sample size — which is a fundamental consideration in weighing

the importance of a study’s findings and conclusions as it serves as an indicator of the

probability of avoiding a Type II error i.e., finding an apparent effect among the sampled

patients in a study where no effect actually exists.

Additional details regarding the strengths and limitations of included publications are

provided in Appendix 3.

Summary of Findings

What is the clinical effectiveness of the off-label use of intravenous or

subcutaneous immunoglobulin for the treatment of solid organ transplant rejection?

Antibody-Mediated Rejection following Kidney Transplant

Renal Function

One RCT20 and one non-randomized, retrospective observational study21 were identified

describing the comparative effect of off-label use of IVIG versus placebo20 and

methylprednisolone21 on renal function in patients with antibody-mediated rejection (AMR)

following kidney transplant. No information regarding SCIG was identified.

The RCT reported change in mean estimated glomerular filtration rate (GFR) at one year of

follow-up in the IVIG + RTX group as −4.2 (±14.4) mL/min per 1.73m2 (P = 0.125) and in

the placebo group, −6.6 (±12.0) mL/min per 1.73m2 (P = 0.248). The difference between

groups was not statistically significant (P = 0.475).20 Nonetheless, the authors suggested

caution in interpreting the results given the limitations of their sample size.20 The non-

randomized, retrospective observational study reported the change in average, absolute

GFR before and after the intervention in the IVIG group as -2.25 mL/min and in the

methylprednisolone (MP) group, -5.26 mL/min. The statistical difference between groups

was not reported. The non-randomized study also reported the results of a generalized

mixed linear model of estimated GFR that found the change in linear slope was significant

in patients receiving IVIG i.e., 0.69 mL/min/month (P < 0.001) but not significant in patients

receiving MP i.e., 0.01 mL/min/month (difference reported qualitatively as not significant

i.e., no P-value). The relative change between groups in linear slope before and after the

interventions were administered was reported as 0.7 mL/min/mo (P < 0.033), suggesting a

significant benefit for the IVIG group.21

Change in mean serum creatinine was measured in both studies using mg/dL. The RCT

reported a change of 0.2 (± 2.1) in the IVIG + RTX group and 0.6 (± 1.1) in the placebo

group — the difference between groups was not statistically significant.20 The non-

randomized study reported only baseline values per group for serum creatinine with no

follow-up data.21


The RCT also reported on several secondary measures of renal function, none of which

demonstrated any statistically significant differences between the IVIG + RTX and placebo

groups.20

Adverse Events

The RCT20 explored adverse events (AEs), recording 26 in the IVIG + RTX group and 28 in

the placebo group — which authors described qualitatively as not different between groups .

In the IVIG + RTX group, five patients required hospitalization for AEs, whereas four

patients in the placebo group were hospitalized for AEs. Diagnoses among hospitalized

patients in the IVIG + RTX group included urinary sepsis, urinary tract infection, fever, and

hyponatremia. In patients who received placebo and were hospitalized for AEs, diagnoses

included acute diverticulitis, acute gastroenteritis with acute renal failure, and esophageal

perforation.20

While the non-randomized study did not pre-specify evaluation of AEs, and did not report

any AEs in the results, the authors indicated that no serious side effects were observed in

patients as a result of receiving IVIG.21

Appendix 4 presents a table of the main study findings and authors’ conclusions.

Limitations

There were a number of limitations with the evidence identified in this review describing off-

label IVIG for the treatment of solid organ transplant rejection. The comparative evidence in

this area was limited, such that two studies were found to be eligible. Additional evidence in

this area is of limited methodological rigour, using non-randomized designs, small sample

sizes and not employing the use of any comparison group against IVIG interventions.

Both of the included studies in this review20,21 examined kidney transplant recipients,

limiting any interpretation about the use of off-label IVIG in solid organ transplant rejection

patients to renal transplant recipients only. Importantly, both studies employed the use of

small sample sizes which necessitates caution in the interpretation of their findings.

Extending from this, the conclusions drawn by authors of the two studies are discordant,

further suggesting that the evidence addressing the use of off-label IVIG in renal transplant

rejection patients remains underdeveloped and that additional, rigourous research is

needed to understand its potential effect.

While the included RCT reported a government ministry as its funding source, the non-

randomized study did not report their source of funding. In addition to limited generalizability

and potential threats to internal and external validity, the lack of a transparent statement of

funding warrants further caution. Consequently, the results of this report should be

interpreted with caution.


Conclusions and Implications for Decision or Policy Making

This review identified two comparative studies evaluating the use of IVIG in renal transplant

patients with AMR. One study was an RCT examining 25 patients and the other was a non-

randomized, retrospective, observational study of 39 patients. Although there is some

description of IVIG addressing antibody-mediated rejection (in particular in kidney

transplant patients) in related literature, it is acknowledged that the potential mechanism of

effect remains uncertain22 and its effectiveness has not been demonstrated in large, clinical

trials.17 No evidence regarding SCIG was identified.

In this review, limited RCT evidence of moderate quality indicates that the use of IVIG

combined with rituximab (RTX) had no statistically significant effect on any study measure

of renal function in patients with antibody-mediated rejection (AMR) when compared

against placebo.20 Authors of the study encouraged caution in the interpretation of the

results due to its small sample size, in particular. Evidence of limited quality in the non-

randomized study indicates that there was no change in absolute average glomerular

filtration rate (GFR) in either patients treated with IVIG or those treated with

methylprednisolone (MP).21 Nonetheless, modeled data indicated a statistically significant

difference in the post-intervention change in linear slope of the glomerular filtration rate

(GFR), favouring patients treated with IVIG. Authors of this study concluded that IVIG

improved renal function in patients with AMR.21

Most other research evaluating IVIG for solid organ transplantation focuses on kidney

transplants in patients with AMR.23-26 Recent studies examining IVIG in the context of solid

organ transplant have been conducted using small samples and single-arm designs

examining various treatment regimens that include IVIG.23-27 This work has similarly

demonstrated variable effects, from some apparent effect on measures of organ function in

some patients23,24,27 to no apparent effect in other patients.25 Consequently, established

clinical benefits remain uncertain25,26 and unrealized.27

In conclusion, while one study in this review suggested a benefit of IVIG for patients with

AMR of kidney transplant, another study of higher quality found no effect. Both studies had

some risk of bias due to uncertain external validity (representativeness) and small sample

size (low power). The study that reported a benefit of IVIG had important, additional

limitations to internal validity (true effect) and no explicitly stated source of funding.

Therefore, results should be interpreted with caution as the clinical effectiveness of IVIG for

kidney transplant remains unclear. Further evidence from larger, long-term studies,

including investigating other types of organ transplants, is necessary to reduce uncertainty.


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immune globulin f or neurologic conditions. Transf us Med Rev . 2007 Apr;21(2 Suppl 1):S57-107.

13. Hume HA, Anderson DR. Guidelines f or the use of intrav enous immune globulin f or hematologic and neurologic conditions. Transf us Med Rev . 2007 Apr;21(2 Suppl 1):S1-S2.

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17. Jordan SC, Toy oda M, Kahwaji J, Vo AA. Clinical aspects of intrav enous immunoglobulin use in solid organ transplant recipients. Am J Transplant. 2011 Feb;11(2):196-202.

18. Of f -label use of intrav enous immunoglobulin f or solid organ transplant rejection, paraneoplastic disorders, or

recurrent miscarriage: clinical ef f ectiveness [Internet] . Ottawa (ON): CADTH; 2017 Nov 7. [cited 2018 Apr 20]. (CADTH rapid response report: summary of abstracts). Available f rom:

https://www.cadth.ca/sites/def ault/files/pdf/htis/2017/RB1154%20Other%20Of f -Label%20IVIG%20Final.pdf

https://medical-dictionary.thefreedictionary.com/solid+organhttps://www.cihi.ca/en/corr-annual-statistics-2007-to-2016https://medlineplus.gov/ency/article/000815.htmhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5349636http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3337620http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778785http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4285166http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1809480https://professionaleducation.blood.ca/en/transfusion/clinical-guide/immune-globulin-productshttps://health-products.canada.ca/dpd-bdpp/index-eng.jsphttp://www.transfusionontario.org/media/IVIG%20Toolkit_COM_2012.pdfhttps://www.cadth.ca/sites/default/files/pdf/htis/2017/RB1154%20Other%20Off-Label%20IVIG%20Final.pdf


19. Downs SH, Black N. The f easibility of creating a checklist f or the assessment of the methodological quality both

of randomised and non-randomised studies of health care interv entions. J Epidemiol Community Health

[Internet]. 1998 Jun [cited 2018 Apr 20];52(6):377-84. Av ailable f rom: http://www.ncbi.nlm.nih.gov /pmc/articles/PMC1756728/pdf /v052p00377.pdf

20. Moreso F, Crespo M, Ruiz JC, Torres A, Gutierrez-Dalmau A, Osuna A, et al. Treatment of chronic antibody

mediated rejection with intrav enous immunoglobulins and rituximab: A multicenter, prospectiv e, randomized,

double-blind clinical trial. Am J Transplant. 2018 Apr;18(4):927-35.

21. Furmanczy k-Zawiska A, Urbanowicz A, Perkowska-Ptasinska A, Baczkowska T, Sadowska A, Nazarewski S, et

al. Human pooled immunoglobulin as treatment of activ e antibody -mediated rejection of transplanted kidney .

Transplant Proc. 2016 Jun;48(5):1446-50.

22. Valenzuela NM, Reed EF. Antibody -mediated rejection across solid organ transplants: manif estations, mechanisms, and therapies. J Clin Inv est [Internet]. 2017 Jun 30 [cited 2018 Apr 20];127(7):2492-504. Av ailable

f rom: http://www.ncbi.nlm.nih.gov /pmc/articles/PMC5490786

23. Ruangkanchanasetr P, Satirapoj B, Termmathurapoj S, Namkhanisorn K, Suay wan K, Nimkietkajorn V, et al.

Intensiv e plasmapheresis and intrav enous immunoglobulin f or treatment of antibody -mediated rejection af ter kidney transplant. Exp Clin Transplant [Internet]. 2014 Aug [cited 2018 Apr 20];12(4):328-33. Av ailable f rom:

http://www.ectrx.org/f orms/ectrxcontentshow.php?doi_id=10.6002/ect.2013.0296&y ear=2014&v olume=12&issue

=4&supplement=0&makale_no=0&spage_number=328&content_ty pe=PDF

24. Cooper JE, Gralla J, Klem P, Chan L, Wiseman AC. High dose intrav enous immunoglobulin therapy f or donor-

specif ic antibodies in kidney transplant recipients with acute and chronic graf t dy sfunction. Transplantation. 2014

Jun 27;97(12):1253-9.

25. Gulleroglu K, Baskin E, Bay rakci US, Turan M, Ozdemir BH, Moray G, et al. Antibody -mediated rejection and treatment in pediatric patients: one center's experience. Exp Clin Transplant [Internet]. 2013 Oct [cited 2018 Apr

20];11(5):404-7. Av ailable f rom:

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26. Gubensek J, Buturov ic-Ponikv ar J, Kandus A, Arnol M, Kov ac J, Marn-Pernat A, et al. Plasma exchange and

intrav enous immunoglobulin in the treatment of antibody -mediated rejection af ter kidney transplantation: a single-

center historic cohort study . Transplant Proc. 2013 May ;45(4):1524-7.

27. Otani S, Dav is AK, Cantwell L, Iv ulich S, Pham A, Paraskev a MA, et al. Ev olv ing experience of treating antibody -mediated rejection f ollowing lung transplantation. Transpl Immunol. 2014 Aug;31(2):75-80.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490786http://www.ectrx.org/forms/ectrxcontentshow.php?doi_id=10.6002/ect.2013.0296&year=2014&volume=12&issue=4&supplement=0&makale_no=0&spage_number=328&content_type=PDFhttp://www.ectrx.org/forms/ectrxcontentshow.php?doi_id=10.6002/ect.2013.0296&year=2014&volume=12&issue=4&supplement=0&makale_no=0&spage_number=328&content_type=PDFhttp://www.ectrx.org/forms/ectrxcontentshow.php?doi_id=10.6002/ect.2012.0242&year=2013&volume=11&issue=5&supplement=0&makale_no=0&spage_number=404&content_type=PDFhttp://www.ectrx.org/forms/ectrxcontentshow.php?doi_id=10.6002/ect.2012.0242&year=2013&volume=11&issue=5&supplement=0&makale_no=0&spage_number=404&content_type=PDF


Appendix 1: Selection of Included Studies

432 citations excluded

24 potentially relevant articles retrieved

for scrutiny (full text, if available)

0 potentially relevant reports retrieved from other sources (grey

literature, hand search)

24 potentially relevant reports

22 reports excluded: -irrelevant population (17)

-irrelevant comparator (5)

2 reports included in review

456 citations identified from electronic

literature search and screened


Appendix 2: Characteristics of Included Publications

Table 2: Characteristics of Included Primary Clinical Studies

First Author,

Publication Year, Country

Study

Design

Population

Characteristics

Intervention and

Comparator(s)

Clinical Outcomes, Measures,

Length of Follow-Up

Moreso,201720 Spain

Double-blind RCT

25 kidney transplant patients with chronic AMR randomized Intervention arm: Mean age = 47 (±13) Female/male = 4/8 Comparison arm: Mean age = 49 (±15) Female/male = 6/7 Setting was described as multi-centre; additional details NR

IVIG and rituximab (RTX) versus placebo Intervention arm: IVIG (0.5 g/kg) every 3 weeks for 4 doses, plus a single dose of rituximab (375 mg/m2) 1 week after the last IVIG dose Comparison arm: Isovolumetric saline solution using the same schedule as the intervention arm

Renal function measured by: Primarily i. Estimated glomerular filtration rate

(GFR) using the Modified Diet in Renal Disease (MDRD) equation (ml/min per 1.73 m2)

ii. Serum creatinine (mg/dL) Secondarily

iii. Proteinuria (g/day) iv. Renal lesions (Banff criteria producing a

histological score) v. Donor-specific antibodies (DSA)

(reported as mean fluorescence intensity (MFI))

vi. Adverse events, including graft loss and/or death

Follow-up = 1 year

Furmanczyk-Zawiska,201621 Poland

Retrospective observational study

39 kidney transplant recipients with AMR enrolled Intervention arm: Mean age = 40.64 yrs (±11.23) Female/male = 6/11 Comparison arm: Mean age = 37.45 (±11.61) Female/male = 12/10 Setting described as single-centre; additional details NR

IVIG versus methylprednisolone (MP) Intervention arm: IVIG (1-3 g/kg) for 2 consecutive days plus IV MP, antihistamine and basic immunosuppression Control arm: IV MP (500 mg) for 3 consecutive days, plus prednisone and basic immunosuppression

Renal function measured by: i. Change in estimated glomerular filtration

rate (GFR) over time using the Modified Diet in Renal Disease (MDRD) formula and modeled using a mixed generalized linear method

ii. Serum creatinine Intervention arm: Mean follow-up = 18.8 mos (range 4.7 to 75.76) Comparison arm: Mean follow-up = 10.12 mos (range 1.88 to 34.11)

AMR = Antibody-mediated rejection; dL = decilitre; DSA = Donor-specif ic antibodies; eGFR = Estimated glomerular f iltration rate; g = grams; GFR =

Glomerular f iltration rate; IgG = Immunoglobulin G; IV = Intravenous; IVIG = Intravenous immunoglobulin; kg = kilogram; MDRD = Modif ied Diet in

Renal Disease; MFI = Mean fluorescence intensity; mg = milligram; m = metre; mos = months; MP = methylprednisolone; NR = not reported; RCT =

randomized controlled trial; RTX = Rituximab; yrs = years


Appendix 3: Critical Appraisal of Included Publications

Table 3: Strengths and Limitations of Clinical Studies using Down's and Black Checklist for measuring study quality19

Strengths Limitations

Randomized Controlled Trial

Moreso, 201720

Reporting

Aim and objectives, main outcomes, patient characteristics, interventions, main findings, random variability, loss to follow-up and probability values clearly reported

Internal validity – bias

Study subjects and outcome assessors were blinded

No evidence of unplanned analyses Follow up duration was standard and consistent

Statistical tests appear appropriate

Compliance with the intervention was reported Outcome measures clearly reported

Internal validity – confounding

Study subjects recruited over the same period of time Study subjects were randomized to treatment

Randomization was concealed

Loss to follow-up accounted for

Reporting

List of principal confounders, distribution of data and adverse events not clearly reported

External validity Representativeness of eligible patients, study subjects and

treatment setting not clearly reported Internal validity – confounding

No information concerning the centre of recruitment per treatment group

No mention of confounding Power Study was underpowered (but this was clearly

acknowledged)

Non-Randomized Study

Furmanczyk-Zawiska, 201621

Reporting

Aim and objectives, main outcomes, patient characteristics and interventions clearly reported

Internal validity – bias No evidence of unplanned analyses

Variability in follow up duration was adjusted for in the analyses

Statistical tests appear appropriate Internal validity – confounding

Patients in both treatment groups recruited from same population

Reporting

List of principal confounders, distribution of data, main findings, random variability and probability values not reported clearly and/or consistently

Adverse events and loss to follow-up not reported External validity

Representativeness of eligible patients and treatment setting not clearly reported

Representativeness of study subjects not reported Internal validity – bias

Study subjects and outcome assessors not blinded Outcome measures not clearly reported

Compliance with the intervention not clearly reported Internal validity – confounding

Study subjects not recruited over the same period of time

Study subjects not randomized to treatment Loss to follow-up not explicitly accounted for

Adjustment for confounding not clearly reported Power Study was underpowered (but this was acknowledged)


Appendix 4: Main Study Findings and Authors’ Conclusions

Table 4: Summary of Findings of Included Primary Clinical Studies

Main Study Findings Authors’ Conclusion

Randomized Controlled Trial

Moreso, 201720

i. Change in mean eGFR at 1 year (mL/min per 1.73 m2)

IVIG o −4.2 ± 14.4 (P = 0.125)

Placebo o −6.6 ± 12.0 (P = 0.248)

Difference between groups o P = 0.475

ii. Change in serum creatinine at 1 year (mg/dL)

IVIG o 0.2 ± 2.1

Placebo o 0.6 ± 1.1


iii. Change in proteinuria at 1 year (mean g/day)

IVIG o 0.9 ± 2.1 (P = NR)

Placebo o 0.9 ± 2.1 (P = NR)


iv. Change in renal lesions at 1 year (Banff scores) IVIG

o Overall score NR (subscale scores only) o No significant change in severity (P = NR)

Placebo o Overall score NR (subscale scores only) o No significant change in severity (P = NR)

Difference between groups: o Banff scores = NS (P = NR)

v. Change in DSA at 1 year (MFI)

IVIG o No significant change (P = NR)

Placebo o No significant change (P = NR)

Difference between groups: o NS (P = NR)

vi. Adverse events (AEs)

IVIG o Total N=26 o Patients with AE requiring hospitalization (N=5)

Urinary sepsis (1) Fever with negative cultures (1) Urinary tract infection (2) Hyponatremia (1)

Placebo

“The primary efficacy variab le was the rate of eGFR decline during the first year and it was not different between the treatment and

placebo groups, suggesting that the combination of IVIG and RTX does not stab ilize renal function in patients with chronic ABMR displaying transplant glomerulopathy.” (p. 932)


Main Study Findings Authors’ Conclusion

o Total N=28 o Patients with AE requiring hospitalization (N=4)

Acute diverticulitis (1) Acute gastroenteritis with acute renal failure

(2) Esophageal perforation with mediastinal

abscess (1)

Difference between groups: o Reported as “not different” (p. 932) (P = NR)

Retrospective Observational Study

Furmanczyk-Zawiska, 201621

i. Change in average absolute estimated GFR (mL/min), pre- and post-intervention

IVIG o -2.25 (P = NS)

MP o -5.26 (P = NS)

Difference between groups NR

ii. Change in linear slope of estimated GFR (mL/min/month)

IVIG o Difference at time of intervention

0.69 (P < 0.01) MP

o Difference at time of intervention 0.01 (P = NS)

Relative slope change, pre- to post-intervention o 0.7 (P < 0.033) (favours the IVIG group)

iii. Serum creatinine

NR

“IVIG improved graft function in renal recipients diagnosed with b iopsy-proven ABMR independently from classic immunologic or nonimmunologic graft function predictors.” (p. 1450)

AE = adverse event; AMR = Antibody-mediated rejection; dL = deciliter; DSA = Donor-specif ic antibodies; eGFR = Estimated glomerular f iltration

rate; g = gram; GFR = Glomerular f iltration rate; IgG = Immunoglobulin G; IVIG = Intravenous immunoglobulin; m = metre; MDRD = Modif ied Diet in

Renal Disease; MFI = Mean fluorescence intensity; min = minute; mL = millilitre; MP = methylprednisolone; NR = not reported; NS = not signif icant;

RCT = randomized controlled trial; RTX = Rituximab


Appendix 5: Additional References of Potential

Interest

Cooper JE, Gralla J, Klem P, Chan L, Wiseman AC. High dose intravenous immunoglobulin

therapy for donor-specific antibodies in kidney transplant recipients with acute and chronic

graft dysfunction. Transplantation. 2014 Jun 27;97(12):1253-9. PubMed: PM24937199

Gubensek J, Buturovic-Ponikvar J, Kandus A, Arnol M, Kovac J, Marn-Pernat A, et al.

Plasma exchange and intravenous immunoglobulin in the treatment of antibody-mediated

rejection after kidney transplantation: a single-center historic cohort study. Transplant Proc.

2013 May;45(4):1524-7. PubMed: PM23726611

Gulleroglu K, Baskin E, Bayrakci US, Turan M, Ozdemir BH, Moray G, et al. Antibody-

mediated rejection and treatment in pediatric patients: one center's experience. Exp Clin

Transplant. 2013 Oct;11(5):404-7. PubMed: PM24128133

Otani S, Davis AK, Cantwell L, Ivulich S, Pham A, Paraskeva MA, et al. Evolving

experience of treating antibody-mediated rejection following lung transplantation. Transpl

Immunol. 2014 Aug;31(2):75-80. PubMed: PM25004453

Ruangkanchanasetr P, Satirapoj B, Termmathurapoj S, Namkhanisorn K, Suaywan K,

Nimkietkajorn V, et al. Intensive plasmapheresis and intravenous immunoglobulin for

treatment of antibody-mediated rejection after kidney transplant. Exp Clin Transplant. 2014

Aug;12(4):328-33. PubMed: PM25095710

Documents

CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL ... OffLab… · IVIG = Intravenous immunoglobulin; SCIG = Subcutaneous immunoglobulin. Exclusion Criteria Articles were excluded